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Abstract Cerium and cerium containing materials have been drawing increasing attentions in industrial and biomedical applications in recent decades. The increased applications of cerium have also increased the risk of human body exposed to cerium ions. Due to its similar ionic radius to calcium(II), cerium(III) have found mainly deposited in the skeletal system. However, the effects of cerium(III) on the bone metabolism homeostasis remain poorly understood. In the present study, the effect of cerium(III) on the osteoclastogenesis which plays a pivotal role in bone metabolism homeostasis was investigated. Cerium(III) could enhance the expression and activity of NADPH oxidase1 (Nox1) leading to the elevation of intracellular reactive oxygen species (ROS) level. The augmentation of ROS level activated the RANKL dependent osteoclasts differentiation pathways resulted in the promotion of osteoclastogenesis, while anions associated with cerium(III) cation have no effects on the differentiation of osteoclasts. The cerium(III) activated osteoclasts exhibited enhanced bone resorption capability. These results provided fundamental information for understanding the potential effects of cerium(III) on the metabolism homeostasis of skeletal system which is of great reference value for future biomedical applications of cerium salts. [ABSTRACT FROM AUTHOR]

Essential metals are vital elements for human biology. Iron, copper, and zinc are all essential for life. Trace metal dyshomeostasis has been linked to cognitive deterioration and in particular to a disturbance in the regulation of copper (Cu), characterized by an increase in serum Cu not bound to ceruloplasmin (nCp-Cu also known as “free” copper). It is thought to play a role in the development of Alzheimer’s disease (AD), the most common form of dementia. Copper homeostasis is finely regulated in our bodies and the expansion of exchangeable nCp-Cu is symptom of the breakdown of this homeostasis, which affects myriad biological pathways. If not structurally bound to enzymes or coordinated by proteins, copper generates free radicals via Haber-Weiss and Fenton reactions. Human Serum Albumin (HSA) is the most abundant serum protein and the main protein exchanging copper in the nCp-Cu pool. Copper coordinated by HSA is in equilibrium with copper coordinated by other small copper chelators circulating in the blood stream in a dynamic and exchangeable manner dependent on environmental osmolarity, oxidation state, pH and compounds’ functions. Albumin is susceptible to glycation starting from Maillard reaction, carbohydrates, in particular glucose, form advanced glycation end-products (AGEs). AGE-albumin is one of this products. Free radicals and free metals in circulation accelerate this cross-linking of protein with carbohydrates. Modified albumins are also significantly less effective than native forms in avoiding the aggregation of Aβ, the main component of the amyloid plaques in the AD brain. The current review aims to provide insight into the coordination chemistry of copper in plasma with a special glance toward the exchangeable copper coordinated by albumin, to explore how aberrant regulations of this interaction are linked to the aetiology of AD. [ABSTRACT FROM AUTHOR]

Although iron and copper are co-ordinately regulated in living cells, the homeostatic effects of each of these metals on the other remain unknown. Here, we show the function of AfMac1, a transcriptional activator of the copper and iron regulons of Aspergillus fumigatus, on the interaction between iron and copper. In addition to the copper-specific AfMac1-binding motif 50-TGTGCTCA-30 found in the promoter region of ctrC, the ironspecific AfMac1-binding motif 50-AT(C/G)NN(A/T)T(A/C)-30 was identified in the iron regulon but not in the copper regulon by ChIP sequence analysis. Furthermore, mutation of the AfMac1-binding motif of sit1 eliminated AfMac1-mediated sit1 up-regulation. Interestingly, the regulation of gene expression in the iron regulon by AfMac1 was not affected by copper and vice versa. AfMac1 localized to the nucleus under iron- or copper-depleted conditions, and AfMac1 was mostly detected in the cytoplasm under iron- or copper-replete conditions. Taken together, these results suggest that A. fumigatus independently regulates iron and copper homeostasis in a manner that involves AfMac1 and mutual interactions. [ABSTRACT FROM AUTHOR]

Meta-analyses show copper dyshomeostasis in Alzheimer's disease. However, a study evaluating copper changes in other neurodegenerative forms of dementia has not yet been performed. In this study, we assessed copper, ceruloplasmin, copper not bound to ceruloplasmin, and copper to ceruloplasmin ratio in 85 patients affected by frontotemporal lobar degeneration (FTLD) and 55 healthy controls. Data were analyzed through multivariate ANOVA models taking into account age and sex as covariates and the stratification for FTLD variants, after calculating power analysis to ensure the reliability of the conclusions drawn. The study revealed no difference between the groups. [ABSTRACT FROM AUTHOR]

ATP7A and ATP7B are Cu+-transporting ATPases of subclass IB and play a fundamental role in intracellular copper homeostasis. ATP7A/B transfer Cu+ ions across the membrane from delivery to acceptor proteins without establishing a free Cu+ gradient. Transfer of copper across the membrane is coupled to ATP hydrolysis. Current measurements on solid supported membranes (SSM) were performed to investigate the mechanism of copper-related charge transfer across ATP7A and ATP7B. SSM measurements demonstrated that electrogenic copper displacement occurs within ATP7A/B following addition of ATP and formation of the phosphorylated intermediate. Comparison of the time constants for cation displacement in ATP7A/B and sarcoplasmic reticulum Ca2+-ATPase is consistent with the slower phosphoenzyme formation in copper ATPases. Moreover, ATP-dependent copper transfer in ATP7A/B is not affected by varying the pH, suggesting that net proton counter-transport may not occur in copper ATPases. Platinum anticancer drugs activate ATP7A/B and are subjected to ATP-dependent vectorial displacement with a mechanism analogous to that of copper. © 2016 IUBMB Life, 69(4):218-225, 2017 [ABSTRACT FROM AUTHOR]

Recent evidence suggests involvement of biometal homeostasis in the pathological mechanisms in Alzheimer's disease (AD). For example, increased intracellular copper or zinc has been linked to a reduction in secreted levels of the AD-causing amyloid-β peptide (Aβ). However, little is known about whether these biometals modulate the generation of Aβ. In the present study we demonstrate in both cell-free and cell-based assays that zinc and copper regulate Aβ production by distinct molecular mechanisms affecting the processing by γ-secretase of its Aβ precursor protein substrate APP-C99. We found that Zn2+ induces APP-C99 dimerization, which prevents its cleavage by γ-secretase and Aβ production, with an IC50 value of 15 μM. Importantly, at this concentration, Zn2+ also drastically raised the production of the aggregation-prone Aβ43 found in the senile plaques ofADbrains and elevated theAβ43:Aβ40 ratio, a promising biomarker for neurotoxicity and AD. We further demonstrate that the APP-C99 histidine residues His-6, His-13, and His-14 control the Zn2+-dependent APP-C99 dimerization and inhibition of Aβ production, whereas the increased Aβ43:Aβ40 ratio is substrate dimerization-independent and involves the known Zn2+ binding lysine Lys-28 residue that orientates the APP-C99 transmembrane domain within the lipid bilayer. Unlike zinc, copper inhibited Aβ production by directly targeting the subunits presenilin and nicastrin in the γ-secretase complex. Altogether, our data demonstrate that zinc and copper differentially modulate Aβ production. They further suggest that dimerization of APP-C99 or the specific targeting of individual residues regulating the production of the long, toxic Aβ species, may offer two therapeutic strategies for preventing AD. [ABSTRACT FROM AUTHOR]

Purpose: Copper (Cu) is an essential trace element; however excess is toxic due to the pro-oxidant activity. Increased intracellular Cu levels in vitreous and monocyte were reported in Eales disease (ED) previously. Copper transporter1 (CTR1) maintains copper homeostasis and hence, we studied the presence of CTR1 in ocular tissues and its role in ED.Methods: Real-time PCR, ELISA and Western blot experiments were performed in donor eyeballs tissues and PBMCs isolated from controls and ED. Immunostaining were performed for CTR1 from donor eyeballs and one ED case.Results: CTR1 protein was expressed in all ocular tissues. PBMCs showed a three-fold increase in CTR1 protein in ED when compared with controls. Retinal sections from ED patients also revealed increased CTR1 protein expression in retinal tissues, compared with control.Conclusions: CTR1 was significantly increased in ED when compared with controls, indicating its considerable role in the ED pathology. [ABSTRACT FROM AUTHOR]

Glutathione ( GSH) is a tripeptide often considered to be the master antioxidant in cells. GSH plays an integral role in cellular redox regulation and is also known to have a role in mammalian copper homeostasis. In vitro evidence suggests that GSH is involved in copper uptake, sequestration and efflux. This study was undertaken to further investigate the roles that GSH plays in neuronal copper homeostasis in vivo, using the model organism Drosophila melanogaster. RNA interference-mediated knockdown of the Glutamate-cysteine ligase catalytic subunit gene ( Gclc) that encodes the rate-limiting enzyme in GSH biosynthesis was utilised to genetically deplete GSH levels. When Gclc was knocked down in all neurons, this caused lethality, which was partially rescued by copper supplementation and was exacerbated by additional knockdown of the copper uptake transporter Ctr1A, or over-expression of the copper efflux transporter ATP7. Furthermore, when Gclc was knocked down in a subset of neuropeptide-producing cells, this resulted in adult progeny with unexpanded wings, a phenotype previously associated with copper dyshomeostasis. In these cells, Gclc suppression caused a decrease in axon branching, a phenotype further enhanced by ATP7 over-expression. Therefore, we conclude that GSH may play an important role in regulating neuronal copper levels and that reduction in GSH may lead to functional copper deficiency in neurons in vivo. [ABSTRACT FROM AUTHOR]

Copper (Cu) is an essential metal for growth and development that has the potential to be toxic if levels accumulate beyond the ability of cells to homeostatically balance uptake with detoxification. One system for Cu acquisition is the integral membrane Cu + transporter, Ctr1, which has been quite well characterized in terms of its function and physiology. The mammalian Ctr2 protein has been a conundrum for the copper field, as it is structurally closely related to the high affinity Cu transporter Ctr1, sharing important motifs for Cu transport activity. However, in contrast to mammalian Ctr1, Ctr2 fails to suppress the Cu-dependent growth phenotype of yeast cells defective in Cu + import, nor does it appreciably stimulate Cu acquisition when over-expressed in mammalian cells, underscoring important functional dissimilarities between the two proteins. Several roles for the mammalian Ctr2 have been suggested both in vitro and in vivo. Here, we summarize and discuss current insights into the Ctr2 protein and its interaction with Ctr1, its functions in mammalian Cu homeostasis and platinum-based chemotherapy. [ABSTRACT FROM AUTHOR]

Copper ions are indispensible to life and maintaining tight control over the homeostasis of copper ions in the body is a prerequisite to sustaining health. Aberrations in normal copper levels, both systemic as well as on a tissue or cellular scale, are implicated in a wide range of diseases, such as Menkes disease, Wilson's disease, Alzheimer's disease, Parkinson's disease and transmissible spongiform encephalopathy (prion diseases). The current understanding of how copper influences these diseases is described. The field of fluorescent copper sensors both functioning via a reaction based mechanism as well as by directly binding copper ions has known an inflation in recent years, and the importance of this field to elucidating the role of copper in cell biology is pointed out. Progress in these tightly interwoven fields has resulted in a better understanding of a number of diseases related to copper imbalances and current developments might open the path for novel and innovating therapies to address these diseases. [ABSTRACT FROM AUTHOR]

Wilson's disease (WD) is a human disorder of copper homeostasis caused by mutations in the copper-transporting ATPase ATP7B. WD is characterized by copper accumulation, predominantly in the liver and brain, hepatic pathology, and wide differences between patients in the age of onset and the spectrum of symptoms. Several factors contribute to the phenotypic variability of WD. The WD-causing mutations produce a wide range of changes in stability, activity, intracellular localization, and trafficking of ATP7B; the nonpathogenic genetic polymorphisms may contribute to the phenotype. In Atp7b−/− mice, a mouse model of WD, an abnormal intracellular distribution of copper in the liver triggers distinct changes in the transcriptome; these mRNA profiles might be used to more specifically define disease progression. The major effect of accumulating copper on lipid metabolism and especially cholesterol homeostasis in mice and humans suggests the importance of fat and cholesterol metabolism as modifying factors in WD. [ABSTRACT FROM AUTHOR]

In Wilson's disease (WD) and related animal models, liver mitochondria are confronted with an increasing copper burden. Physiologically, the mitochondrial matrix may act as a dynamic copper buffer that efficiently distributes the metal to its copper-dependent enzymes. Mitochondria are the first responders in the event of an imbalanced copper homeostasis, as typical changes of their structure are among the earliest observable pathological features in WD. These changes are due to accumulating copper in the mitochondrial membranes and can be reversed by copper-chelating therapies. At the early stage, copper-dependent oxidative stress does not seem to occur. On the contrary, however, when copper is massively deposited in mitochondria, severe structural and respiratory impairments are observed upon disease progression. This provokes reactive oxygen species and consequently causes the mitochondrial membranes to disintegrate, which triggers hepatocyte death. Thus, in WD mitochondria are prime targets for copper, and the excessive copper burden causes their destruction, subsequently provoking tissue failure and death. [ABSTRACT FROM AUTHOR]

Abstract: Over 170 mutations in superoxide dismutase-1 (SOD1) have been linked to amyotrophic lateral sclerosis (ALS). The properties of SOD1 mutants differ considerably including copper-binding abilities. Nevertheless, they cause the same disease phenotype, suggesting a common neurotoxic pathway. We have previously reported that copper homeostasis is disturbed in spinal cords of SOD1G93A mice. However, it is unknown whether copper dyshomeostasis is induced by other SOD1 mutants. Using the additional mouse strains SOD1G127insTGGG, SOD1G85R, and SOD1D90A, which express SOD1 mutants with different copper-binding abilities, we show that copper dyshomeostasis is common to SOD1 mutants. The SOD1 mutants shifted the copper trafficking systems toward copper accumulation in spinal cords of the mice. Copper contents bound to the SOD1 active site varied considerably between SOD1 mutants. Still, copper bound to other ligands in the spinal cord were markedly increased in all. Zinc was also increased, whereas there were no changes in magnesium, calcium, aluminum, manganese and iron. Further support for a role of copper dyshomeostasis in ALS was gained from results of pharmacological intervention. Ammonium tetrathiomolybdate (TTM), a copper chelating agent, prolonged survival and slowed the disease progression of SOD1G93A mice, even when the treatment was started after the disease onset. TTM markedly attenuated pathology, including the loss of motor neurons and axons, and atrophy of skeletal muscles. Additionally, TTM decreased amounts of SOD1 aggregates. We propose that pharmacological agents that are capable of modulating copper dyshomeostasis, such as TTM, might be beneficial for the treatment of ALS caused by SOD1 mutations. [Copyright &y& Elsevier]

Dietary copper is essential for multicellular organisms. Copper is redox active and required as a cofactor for enzymes such as the antioxidant Superoxide Dismutase 1 (SOD1). Copper dyshomeostasis has been implicated in Alzheimer’s disease. Mutations in the presenilin genes encoding PS1 and PS2 are major causes of early-onset familial Alzheimer’s disease. PS1 and PS2 are required for efficient copper uptake in mammalian systems. Here we demonstrate a conserved role for presenilin in dietary copper uptake in the fly Drosophila melanogaster. Ubiquitous RNA interference-mediated knockdown of the single Drosophila presenilin (PSN) gene is lethal. However, PSN knockdown in the midgut produces viable flies. These flies have reduced copper levels and are more tolerant to excess dietary copper. Expression of a copper-responsive EYFP construct was also lower in the midgut of these larvae, indicative of reduced dietary copper uptake. SOD activity was reduced by midgut PSN knockdown, and these flies were sensitive to the superoxide-inducing chemical paraquat. These data support presenilin being needed for dietary copper uptake in the gut and so impacting on SOD activity and tolerance to oxidative stress. These results are consistent with previous studies of mammalian presenilins, supporting a conserved role for these proteins in mediating copper uptake. [ABSTRACT FROM AUTHOR]

The high-affinity copper transporter (Ctr1; SCLC31A1) plays an important role in regulating copper homeostasis because copper is an essential micronutrient and copper deficiency is detrimental to many important cellular functions, but excess copper is toxic. Recent research has revealed that human copper homeostasis is tightly controlled by interregulatory circuitry involving copper, Sp1, and human (hCtr1). This circuitry uses Sp1 transcription factor as a copper sensor in modulating hCtr1 expression, which in turn controls cellular copper and Sp1 levels in a 3-way mutual regulatory loop. Posttranslational regulation of hCtr1 expression by copper stresses has also been described in the literature. Because hCtr1 can also transport platinum drugs, this finding underscores the important role of hCtr1 in platinum-drug sensitivity in cancer chemotherapy. Consistent with this notion is the finding that elevated hCtr1 expression was associated with favorable treatment outcomes in cisplatin-based cancer chemotherapy. Moreover, cultured cell studies showed that elevated hCtr1 expression can be induced by depleting cellular copper levels, resulting in enhanced cisplatin uptake and its cell-killing activity. A phase I clinical trial using a combination of trientine (a copper chelator) and carboplatin has been carried out with encouraging results. This review discusses new insights into the role of hCtr1 in regulating copper homeostasis and explains how modulating cellular copper availability could influence treatment efficacy in platinum-based cancer chemotherapy through hCtr1 regulation. [ABSTRACT FROM AUTHOR]

Abstract: Copper (Cu) ion availability in tissues and cells must be closely regulated within safe limits by Cu transporters and chaperones. Astrocytes play key roles in metal homeostasis and distribution in the brain that are only partially understood. The purpose of this study was to define the role that the protein chaperone Hspa5, also known as Grp78, plays in Cu homeostasis in astrocytes. First passage cultures of primary astrocytes from neonatal rats and cultures of the C6 rat glioma cells were used as models. We found that the level of Cu accumulation in astrocyte cultures increased with Cu concentrations in the medium, and Cu treatment significantly reduced cellular levels of iron (Fe), manganese (Mn) and zinc (Zn). Cu accumulation specifically induced protein expression of Hspa5 but not metallothioneins (MTs) in astrocytes. In C6 cells, Hspa5 was identified as one component of a Cu-binding complex and shown to directly bind Cu. However, the level of Hspa5 expression was not proportional to Cu accumulation in astrocytes and C6 cells: astrocytes expressed low protein levels of Hspa5 compared to C6 cells but accumulated significantly more Cu than did C6 cells. Consistent with this finding, astrocytes expressed a lower level of the Cu-extruding protein Atp7a than did C6 cells, and depletion of Hspa5 by RNA interference resulted in significantly increased Cu accumulation and induction of MT1/2 expression. These data demonstrate that Hspa5 is involved in Cu homeostasis in astrocytes but not as a Cu storage protein. [Copyright &y& Elsevier]

Background: Different systems contributing to copper homeostasis in bacteria have been described in recent years involving periplasmic and transport proteins that provide resistance via metal efflux to the extracellular media (CopA/Cue, Cus, Cut, and Pco). The participation of these proteins in the assembly of membrane, periplasmic and secreted cuproproteins has also been postulated. The integration and interrelation of these systems and their apparent redundancies are less clear since they have been studied in alternative systems. Based on the idea that cellular copper is not free but rather it is transferred via protein-protein interactions, we hypothesized that systems would coevolve and be constituted by set numbers of essential components. Results: By the use of a phylogenomic approach we identified the distribution of 14 proteins previously characterized as members of homeostasis systems in the genomes of 268 gamma proteobacteria. Only 3% of the genomes presented the complete systems and 5% of them, all intracellular parasites, lacked the 14 genes. Surprisingly, copper homeostatic pathways did not behave as evolutionary units with particular species assembling different combinations of basic functions. The most frequent functions, and probably because of its distribution the most vital, were copper extrusion from the cytoplasm to the periplasm performed by CopA and copper export from the cytoplasm to the extracellular space performed by CusC, which along with the remaining 12 proteins, assemble in nine different functional repertoires. Conclusions: These observations suggest complex evolutionary dynamics and still unexplored interactions to achieve copper homeostasis, challenging some of the molecular transport mechanism proposed for these systems. [ABSTRACT FROM AUTHOR]

Canine copper toxicosis is an autosomal recessive disorder characterized by hepatic copper accumulation resulting in liver fibrosis and eventually cirrhosis. We have identified COMMD1 as the gene underlying copper toxicosis in Bedlington terriers. Although recent studies suggest that COMMD1 regulates hepatic copper export via an interaction with the Wilson disease protein ATP7B, its importance in hepatic copper homeostasis is ill-defined. In this study, we aimed to assess the effect of Commd1 deficiency on hepatic copper metabolism in mice. Liver-specific Commd1 knockout mice (Commd1Δhep) were generated and fed either a standard or a copper-enriched diet. Copper homeostasis and liver function were determined in Commd1Δhep mice by biochemical and histological analyses, and compared to wild-type littermates. Commd1Δhep mice were viable and did not develop an overt phenotype. At six weeks, the liver copper contents was increased up to a 3-fold upon Commd1 deficiency, but declined with age to concentrations similar to those seen in controls. Interestingly, Commd1Δhep mice fed a copper-enriched diet progressively accumulated copper in the liver up to a 20-fold increase compared to controls. These copper levels did not result in significant induction of the copper-responsive genes metallothionein I and II, neither was there evidence of biochemical liver injury nor overt liver pathology. The biosynthesis of ceruloplasmin was clearly augmented with age in Commd1Δhep mice. Although COMMD1 expression is associated with changes in ATP7B protein stability, no clear correlation between Atp7b levels and copper accumulation in Commd1Δhep mice could be detected. Despite the absence of hepatocellular toxicity in Commd1Δhep mice, the changes in liver copper displayed several parallels with copper toxicosis in Bedlington terriers. Thus, these results provide the first genetic evidence for COMMD1 to play an essential role in hepatic copper homeostasis and present a valuable mouse model for further understanding of the molecular mechanisms underlying hepatic copper homeostasis. [ABSTRACT FROM AUTHOR]

Abstract: Maintaining brain Cu homeostasis is vital for normal brain function. The role of systemic Fe deficiency (FeD) or overload (FeO) due to metabolic diseases or environmental insults in Cu homeostasis in the cerebrospinal fluid (CSF) and brain tissues remains unknown. This study was designed to investigate how blood-brain barrier (BBB) and blood-SCF barrier (BCB) regulated Cu transport and how FeO or FeD altered brain Cu homeostasis. Rats received an Fe-enriched or Fe-depleted diet for 4weeks. FeD and FeO treatment resulted in a significant increase (+55%) and decrease (−56%) in CSF Cu levels (p<0.05), respectively; however, neither treatment had any effect on CSF Fe levels. The FeD, but not FeO, led to significant increases in Cu levels in brain parenchyma and the choroid plexus. In situ brain perfusion studies demonstrated that the rate of Cu transport into the brain parenchyma was significantly faster in FeD rats (+92%) and significantly slower (−53%) in FeO rats than in controls. In vitro two chamber Transwell transepithelial transport studies using primary choroidal epithelial cells revealed a predominant efflux of Cu from the CSF to blood compartment by the BCB. Further ventriculo-cisternal perfusion studies showed that Cu clearance by the choroid plexus in FeD animals was significantly greater than control (p<0.05). Taken together, our results demonstrate that both the BBB and BCB contribute to maintain a stable Cu homeostasis in the brain and CSF. Cu appears to enter the brain primarily via the BBB and is subsequently removed from the CSF by the BCB. FeD has a more profound effect on brain Cu levels than FeO. FeD increases Cu transport at the brain barriers and prompts Cu overload in the CNS. The BCB plays a key role in removing the excess Cu from the CSF. [Copyright &y& Elsevier]

Abstract: The essentiality and redox-activity of copper make it indispensable in the mammalian system. However, a comprehensive understanding of copper metabolism and function has not been achieved. Copper chelators have been used as an approach to provide insights into copper acquisition, distribution, and disposition at both the cellular and organism level. Unfortunately, the understanding of effective copper chelators is predominantly based upon their chemical structures and their reactions with copper. The understanding of the efficacy of copper chelators in the biological system has been equivocal, thereby leading to under- or misleading-utilization of these agents in clinical and experimental approaches. Current use of copper chelators in vivo almost exclusively either limits the availability or focuses on the removal of copper in mammalian organ system. There are at least two aspects of copper chelators that are yet to be explored. First, copper chelators preferentially bind either cuprous or cupric. As a result, they potentially modulate copper redox-activity without removing copper from the system. Second, copper chelators are characterized as either membrane-permeable or -impermeable, thus would serve as an organ-selective copper delivery or deprivation system to manipulate the biological function of copper. Here we review clinically relevant copper chelators that have been experimentally or clinically studied for their role in manipulation of copper metabolism and function, paying critical attention to potentially more valuable usage of these agents. [Copyright &y& Elsevier]

Accumulation of the amyloid β peptide in the cortical and hippocampal regions of the brain is a major pathological feature of Alzheimer disease. Amyloid β peptide is generated from the sequential protease cleavage of the amyloid precursor protein (APP). We reported previously that copper increases the level of APP at the cell surface. Here we report that copper, but not iron or zinc, promotes APP trafficking in cultured polarized epithelial cells and neuronal cells. In SH-SY5Y neuronal cells and primary cortical neurons, copper promoted a redistribution of APP from a perinuclear localization to a wider distribution, including neurites. Importantly, a change in APP localization was not attributed to an up-regulation of APP protein synthesis. Using live cell imaging and endocytosis assays, we found that copper promotes an increase in cell surface APP by increasing its exocytosis and reducing its endocytosis, respectively. This study identifies a novel mechanism by which copper regulates the localization and presumably the function of APP, which is of major significance for understanding the role of APP in copper homeostasis and the role of copper in Alzheimer disease. [ABSTRACT FROM AUTHOR]

Abstract: Copper is essential to mammalian physiology, and its homeostasis is tightly regulated. In humans, genetic defects in copper excretion result in copper overload and Wilson''s disease (WD). Previous studies on the mouse model for WD (Atp7b − /−) revealed copper accumulation in hepatic nuclei and specific changes in mRNA profile prior to the onset of pathology. To find a molecular link between nuclear copper elevation and changes in hepatic transcriptome, we utilized quantitative ionomic and proteomic approaches. X-ray fluorescence and inductively coupled plasma mass spectrometry analysis indicate that copper in the Atp7b −/− nucleus, while highly elevated, does not markedly alter nuclear ion content. Widespread protein oxidation is also not observed, although the glutathione reductase SelH is upregulated, likely to maintain redox balance. We further demonstrate that accumulating copper affects the abundance and/or modification of a distinct subset of nuclear proteins. These proteins populate pathways that are most significantly associated with RNA processing. An alteration in splicing pattern was observed for hnRNP A2/B1, itself the RNA shuttling factor and spliceosome component. Analysis of hnRNP A2/B1 mRNA and protein revealed an increased retention of exon 2 and a selective 2-fold upregulation of a corresponding protein splice variant. Mass spectrometry measurements suggest that the nucleocytoplasmic distribution of RNA binding proteins, including hnRNP A2/B1, is altered in the Atp7b −/− liver. We conclude that remodeling of the RNA processing machinery is an important component of cell response to elevated copper that may guide pathology development in the early stages of WD. [Copyright &y& Elsevier]

Abstract: Copper is an essential micronutrient involved in a variety of biological processes indispensable to sustain life. At the same time, it can be toxic when present in excess, the most noticeable chronic effect being liver damage. Potent, efficient regulatory mechanisms control copper absorption in the digestive tract and copper biliary excretion; absorption ranges between 12 and 60% in humans, depending on Cu intake, presence of other factors in the diet that may promote or inhibit its absorption and on the copper status of the individual. Current evidence suggests that copper deficiency may be more prevalent than previously thought, while copper toxicity is uncommon under customary daily life conditions. Menkes syndrome and Wilson disease are genetic conditions associated with severe copper deficiency and severe copper toxicity, respectively. Effects of milder degrees of copper deficiency and excess copper exposure are not well described, mainly due to lack of sensitive and specific indicators; serum copper concentration and ceruloplasmin are the most frequently used indicators, but they only detect rather intense changes of copper status. Of the many proteins assessed as potential markers of copper status the chaperone of Zn–Cu superoxide dismutase (CCS1) has yielded promising results; data on its performance under different conditions are needed to confirm its use as an indicator of early copper deficiency. Defining copper requirements and upper safe limits of consumption (UL) is a complex process since there are adverse health consequences from both copper deficiency and copper excess (U shape curve). The regulatory framework for risk assessment of essential trace elements introduced by the International Programme on Chemical Safety (IPCS) has proposed a homeostatic model to determine the Adequate Range of Oral Intake (AROI) of essential trace elements; the nadir of the resulting U shape curve serves to define the AROI. At this range of intake physiological mechanisms allow for normal homeostasis and basically, there are no detectable adverse effects. At present, Recommended Dietary Intakes (DRIs) and Adequate Intakes (AIs) are used to recommend copper intakes at different ages and life situations. Evidence obtained in humans and non-human primates presented here suggest that current copper UL should be re evaluated. Developing the scientific basis for a copper UL and evaluating the relevance of copper deficiency globally are future key challenges for copper researchers. [Copyright &y& Elsevier]

We previously detected a membrane-bound, copper-containing oxidase that may be involved in iron efflux in BeWo cells, a human placental cell line. We have now identified a gene encoding a predicted multicopper ferroxidase (MCE) with a putative C-terminal membrane-spanning sequence and high sequence identity to hephaestin (Heph) and ceruloplasmin (Cp), the other known vertebrate MCF. Molecular modeling revealed conservation of all type I, II, and Ill copper-binding sites as well as a putative iron-binding site. Protein expression was observed in multiple diverse mouse tissues, including placenta and mammary gland, and the expression pattern was distinct from that of Cp and Heph. The protein possessed ferroxidase activity, and protein levels decreased in cellular copper deficiency. Knockdown with small interfering RNA in BeWo cells indicates that this gene represents the previously detected oxidase. We propose calling this new member of the MCF family "zyklopen." [ABSTRACT FROM AUTHOR]

Abstract: Alzheimer''s disease (AD) is a progressive neurodegenerative disease characterized by the dys-homeostasis of biometal metabolism, the extracellular accumulation of neurotoxic amyloid-β (Aβ) peptide, the intracellular accumulation of hyperphosphorylated tau and the loss of synapses. Copper plays a key role in AD development. The Aβ peptide and amyloid precursor protein (APP), the parental molecule of Aβ, are modulated by copper in the brain. Increased copper concentration has been found in the AD brain that implies that copper may participate in the pathophysiology of AD. Copper can bind to APP and Aβ, then affects the structure and toxic of APP and Aβ. Some researchers have reported that copper could affect the formation of β-sheet structure that is widely accepted as toxic secondary structure of Aβ. This review explores the role of copper on the conformation and aggregation of Aβ, and the copper-induced neuroactive mechanisms. Copper may be involved in the following pathways to affect the neuroactivation of Aβ: (1) change of the secondary structure of Aβ; (2) induction of oxidative stress in AD brains, and (3) regulation of cellular signal pathway. Thus, correcting brain copper imbalance may represent a relevant therapeutic target for Alzheimer''s disease. [Copyright &y& Elsevier]

Abstract: Information about the health risks or the subtle adverse health effects that might be associated with low-level lead exposure on micronutrient metabolism are scarce in the literature. The present work investigated the subtle adverse health effects of exposure to progressively low levels of lead on the metabolism of two micronutrients, copper and zinc in different tissues of the rat. Rats were exposed to 200, 300 and 400ppm lead in their drinking water for 12 weeks. Lead, copper and zinc concentrations were determined in blood, liver, kidney, heart, spleen and brain of the animals. While the imbalance in zinc metabolism was characterized by a deposition of zinc in the kidney and to a lesser extent in the heart of the animals, imbalance in copper metabolism was characterized by a depletion of blood and splenic copper concentrations as well as renal and cardiac accumulation of copper. Hepatic and brain copper and zinc contents, together with blood zinc were not affected by the 12-week lead exposure. A linear relationship was observed between lead dose and lead accumulation in the spleen, whereas a non-linear relationship was observed between lead dose and lead accumulation in blood, liver, kidney and heart. Our findings indicate that exposure to progressively low-level lead concentrations results in imbalance in copper and zinc in the organism and this might be a factor in propensity toward behavioral disorders observed in lead exposure. [Copyright &y& Elsevier]

Interactions between the essential dietary metals, iron and copper, have been known for many years. This review highlights recent advances in iron-copper interactions with a focus on tissues and cell types important for regulating whole-body iron and copper homeostasis. Cells that mediate dietary assimilation (enterocytes) and storage and distribution (hepatocytes) of iron and copper are considered, along with the principal users (erythroid cells) and recyclers of red cell iron (reticuloendothelial macrophages). Interactions between iron and copper in the brain are also discussed. Many unanswered questions regarding the role of these metals and their interactions in health and disease emerge from this synopsis, highlighting extensive future research opportunities. [ABSTRACT FROM AUTHOR]

Copper-transporting ATPase ATP7B is essential for human copper homeostasis and normal liver function. ATP7B has six N-terminal metal-binding domains (MBDs) that sense cytosolic copper levels and regulate ATP7B. The mechanism of copper sensing and signal integration from multiple MBDs is poorly understood. We show that MBDs communicate and that this communication determines the oxidation state and conformation of the entire N-terminal domain of ATP7B (N-ATP7B). Mutations of copper-coordinating Cys to Ala in any MBD (2, 3, 4, or 6) change the N-ATP7B conformation and have distinct functional consequences. Mutating MBD2 or MBD3 causes Cys oxidation in other MBDs and loss of copper binding. In contrast, mutation of MBD4 and MBD6 does not alter the redox status and function of other sites. Our results suggest that MBD2 and MBD3 work together to regulate access to other metal-binding sites, whereas MBD4 and MBD6 receive copper independently, downstream of MBD2 and MBD3. Unlike Ala substitutions, the Cys-to-Ser -mutation-in--MBD2 preserves the conformation and reduced state of N-ATP7B, suggesting that hydrogen bonds contribute to interdomain communications. Tight coupling between MBDs suggests a mechanism by which small changes in individual sites (induced by copper binding or mutation) result in stabilization of distinct conformations of the entire N-ATP7B and altered exposure of sites for interactions with regulatory proteins. [ABSTRACT FROM AUTHOR]

A breakdown in homeostasis of redox-active metals represents an important factor for neurodegeneration. We have used EPR spectroscopy and BMPO spin-trap to investigate the catalytic properties and ligand modulation of redox activity of copper and iron in human cerebrospinal fluid (CSF). In contrast to iron, copper supplementation provoked a statistically significant increase in hydroxyl free radical generation in CSF treated with H2O2. However, in a binary copper/iron containing Fenton system, iron catalytically activated copper. The chelator EDTA, which represents a model of physiological metal ligands, completely prevented copper's redox activity in CSF, while iron chelation led to a significant increase in hydroxyl radical generation, indicating that copper and iron do not only have diverse catalytic properties in the CSF but also that their redox activities are differently modulated by ligands. The application of DDC reduced hydroxyl radical generation in the CSF containing catalytically active metals (free Cu2+ or Fe3+-EDTA complex). We conclude that chelators, such as DDC, are capable of preventing the prooxidative activity of both metals and may be suitable for reducing hydroxyl radical formation in certain pathophysiological settings. [ABSTRACT FROM AUTHOR]

The transition metal copper is an essential trace element involved in many enzymatic processes that require redox-chemistry. The redox-activity of copper is potentially harmful. Severe imbalance of copper homeostasis can occur with some hereditary disorders of copper metabolism. Copper is acquired from the diet by intestinal absorption and is subsequently distributed throughout the body. The regulation of intestinal copper absorption to maintain whole-body copper homeostasis is currently poorly understood. This review evaluates novel findings regarding the molecular mechanism of intestinal copper uptake. The role of recently identified transporters in enterocyte copper uptake and excretion into the portal circulation is described, and the regulation of dietary copper uptake during physiological and pathophysiological conditions is discussed. [ABSTRACT FROM AUTHOR]

Background: The Copper Metabolism MURR1 Domain containing 1 protein COMMD1 has been associated with copper homeostasis, NF-κB signaling, and sodium transport. Recently, we identified COMMD1 as a novel protein in HIF-1 signaling. Mouse embryos deficient for Commd1 have increased expression of hypoxia/HIF-regulated genes i.e. VEGF, PGK and Bnip3. Hypoxia-inducible factors (HIFs) are master regulators of oxygen homeostasis, which control angiogenesis, erythropoiesis, glycolysis and cell survival/proliferation under normal and pathologic conditions. Although HIF activity is mainly controlled by ubiquitination and protein degradation by the von Hippel Lindau (pVHL) tumor suppressor gene other mechanisms have recently been identified that regulate HIF signaling independently of pVHL. Principal Findings: Here we characterized the mechanism by which COMMD1 regulates HIF-1α protein degradation. We show that COMMD1 competes with the chaperone heat shock protein HSP90β for binding to the NH2-terminal DNAbinding and heterodimerization domain of HIF-1α to regulate HIF-1α stability together with HSP70. Inhibition of HSP90 activity with 17-Allylamino-17-demethoxygeldanamycin (17-AAG) increased COMMD1-mediated HIF-1α degradation independent of ubiquitin and pVHL. Conclusion/Significance: These data reveal a novel role for COMMD1 in conjunction with HSP90β/HSP70 in the ubiquitin and O2-independent regulation of HIF-1α. [ABSTRACT FROM AUTHOR]

Abstract: Copper dyshomeostasis is responsible for the neurological symptoms observed in the genetically inherited copper-dependent disorders (e.g., Menkes’ and Wilson''s diseases), but it has been also shown to have an important role in neurodegenerative diseases such as Alzheimer disease, prion diseases, Parkinson''s disease and amyotrophic lateral sclerosis. It is widely accepted that increased extracellular copper levels contribute to neuronal pathogenic process by increasing the production of dangerous radical oxygen species, but the existence of other molecular mechanisms explaining copper neurotoxicity has not been investigated yet. By using a cellular model based on hypothalamic GN11 cultured neurons exposed to copper supplementation and by analysing the cell conditioned media, we try here to identify new molecular events explaining the association between extracellular copper accumulation and neuronal damages. We show here that increased extracellular copper levels produce a wide complex of alterations in the neuronal extracellular environment. In particular, copper affects the secretion of molecules involved in the protection of neurons against oxidative stress, such as cyclophilin A (CypA), or of molecules capable of shifting neuronal cells towards a pro-inflammatory state, such as IL-1α, IL-12, Rantes, neutrophil gelatinase-associated lipocalin (NGAL) and secreted protein acidic and rich in cysteine (SPARC). Copper pro-inflammatory properties have been confirmed by using primary neurons. [Copyright &y& Elsevier]

Abstract: Amyloid precursor protein (APP) is a transmembrane glycoprotein widely expressed in mammalian tissues and plays a central role in Alzheimer’s disease. However, its physiological function remains elusive. Cu2+ binding and reduction activities have been described in the extracellular APP135–156 region, which might be relevant for cellular copper uptake and homeostasis. Here, we assessed Cu2+ reduction and 64Cu uptake in two human HEK293 cell lines overexpressing APP. Our results indicate that Cu2+ reduction increased and cells accumulated larger levels of copper, maintaining cell viability at supra-physiological levels of Cu2+ ions. Moreover, wild-type cells exposed to both Cu2+ ions and APP135–155 synthetic peptides increased copper reduction and uptake. Complementation of function studies in human APP751 transformed Fre1 defective Saccharomyces cerevisiae cells rescued low Cu2+ reductase activity and increased 64Cu uptake. We conclude that Cu2+ reduction activity of APP facilitates copper uptake and may represent an early step in cellular copper homeostasis. [Copyright &y& Elsevier]

Background: Preeclampsia is a form of high blood pressure with proteinuria manifested during pregnancy, it is a common major complication causing significant morbidity and mortality; however, its etiology is unknown. Moreover, data on mineral and trace elements homeostasis and on cation pattern during pregnancy are conflicting. Also, the status of ionized calcium and magnesium during pregnancy and its complication, preeclampsia, has not been described adequately. Objective: to demonstrate the pattern of minerals and trace elements during preeclampsia with respect to normal pregnancy. Subject and methods: the present study is a cross-sectional case-control study included measurement of minerals (calcium and magnesium) in 60 patients with preeclampsia. They were classified into two groups according to the gestational age: o Preeclamptics in the second trimester G1: (n=30). Preeclamptics in the third trimester G2: (n=30,). The results are compared with 60 apparently healthy pregnant controls. They were classified according to the gestational age into two groups: Pregnants in the second trimester G3: (n=30). Pregnants in the third trimester G4: (n=30). Results: show that serum corrected calcium, serum magnesium and serum zinc were significantly reduced accompanied by significant high serum copper in pre-eclamptics when compared with that of normal pregnants. Conclusion : preeclamptics (in different gestational age groups) altered mineral and trace element status when compared with healthy pregnants matched with their age and gestational age. All preeclamptics had certain factors that reduce vasodilation, enhance vasospasm and trigger oxidative stress supported by the finding of low level of ionized magnesium (which is essential for maintenance of vascular tone), low ionized calcium level (which is essential for the synthesis of endothelial-derived NO), high copper level (which generates highly reactive oxygen species) and low zinc level (which is essential for antioxidant function). [ABSTRACT FROM AUTHOR]

Bacillus subtilisCopZ is a copper (Cu) chaperone that binds and delivers Cu to intracellular targets to maintain cellular Cu homeostasis. Like Cu chaperones from other organisms, including the human homologue Atox1, CopZ has the ferredoxin-like fold and binds Cu(I) via two Cys in a conserved M11X12C13X14X15C16motif located in a solvent-exposed loop. Here, we have performed extensive molecular dynamics simulations on strategic CopZ variants to reveal structural and dynamic roles of three residues near and in the Cu loop (i.e., Met11, Ser12, and Tyr65). Met11 is conserved in all Cu chaperones, whereas Ser12 and Tyr65 are exchanged for Thr and Lys in eukaryotes like Atox1. Therefore, our simulations included apo and holo forms of Met11Ala, Ser12Ala, and Tyr65Ala, as well as Ser12Thr and Tyr65Lys, CopZ variants. We have discovered that the conserved Met is solvent exposed and important for optimal Cu-loop flexibility in the apo form of CopZ but is buried in the core and aids in packing of the fold in holo-CopZ. Ser12 and Tyr65 are important for assuring Cu-loop flexibilityin the apo form; in the Cu-bound form, these residues participate in stabilizing electrostatic networks. The two eukaryotic residues tested are not good substitutes for the prokaryotic counterparts in CopZ. By comparisons to data for Atox1, we conclude that common residues (like Met) and unique residues (like Ser12 and Tyr65 in CopZ) have evolved differentially in prokaryotic and eukaryotic Cu chaperones to tune the flexibility of the Cu loop of the apo form and to provide electrostatic Cu-site stabilization of the holo form. [ABSTRACT FROM AUTHOR]

Cu being a transition metal is ubiquitously engaged in biological systems to derive electrons through its participation in several enzymatic reactions. Upon bestowing the significance of Cu in biological systems, an elaborate mechanism is set forth by nature for maintaining Cu homeostasis. As a consequence, a wide variety of proteins viz., family of Cu bearing proteins, cuproenzymes, Cu transporters and Cu chaperone proteins have been manifested for enabling Cu to show its relevance in biological health. In addition, understanding the role of Cu in hepatic and neuronal functions and also in angiogenesis keeps progressing with the advent of novel molecular tools. The studies on genetic defects in Cu metabolism causing abnormalities are providing insights leading to the possible prognostic cues to alleviate the sufferings. [ABSTRACT FROM AUTHOR]

COMM Domain-containing or COMMD proteins are a recently discovered group of factors defined by the presence of a unique motif in their extreme carboxy termini (Copper metabolism MURR1, or COMM domain). This protein family is comprised of ten members which are widely conserved throughout evolution and share certain functional properties. At the present time, a number of seemingly discrete functions have been ascribed to these factors. These include the regulation of such events as the activity of the transcription factor NF-κB, copper homeostasis, the function of the epithelial sodium channel, and cell proliferation. A unifying mechanism that would explain all these events is lacking at the moment, but recent studies suggest that regulation of the ubiquitin pathway may be the basis of many of the functions of the COMMD protein family. [ABSTRACT FROM AUTHOR]

One-third of the world's population is at risk of zinc deficiency. It has been hypothesized that low serum/plasma zinc may contribute to alteration of brain Zn homeostasis and thus lead to various psychological disorders. This study was designed to evaluate serum zinc (Zn) as well as copper (Cu) concentrations in patients with Bipolar I Disorder (BID) in our community to support the findings on the possible association of Zn in neuropsychological functions. Participants included 30 BID patients with different phases of mania and depression and 30 healthy controls. Results indicated the mean serum Zn level of the BID group was significantly lower than that of controls (P< 0.0001). Similar results were obtained for Cu. These findings suggest a possible association of Zn levels on neuropsychological dysfunction. [ABSTRACT FROM AUTHOR]

The article presents a scientific research which focuses on the alteration of copper physiology in mice overexpressing ATP7A, a human Menkes protein. Transgenic mice expressing ATP7A from chicken β -actin composite promoter were used to fully examine the role of ATP7A. Researchers gave special interest in the topic due to the importance of copper homeostatic mechanisms in genetic disorders like Menkes and Wilson diseases.

AβPP is involved in Cu homeostasis in mouse and man. In vitro observations and in vivo data obtained from AβPP mouse models at least provide strong evidence that AβPP and Aβ overproduction enables intracellular Cu to be transported out of the cell. The increased Cu efflux seems to lead to a Cu deficiency and a subsequently reduced SOD-1 activity. Studies have shown that a disturbed metal-ion homeostasis with elevated serum Cu levels occurs in Alzheimer and Down's patients and lowered levels in post-mortem AD brain. We conclude that bioavailable Cu has beneficial and specific effects in Alzheimer's disease transgenic mice, and suggest that our observation can be regarded as a proof-of-concept for a prophylactic approach to overcome the observed CNS Cu deficiency in the brain of Alzheimer's disease patients. [ABSTRACT FROM AUTHOR]

We previously noted strong induction of genes related to intestinal copper homeostasis (Menkes Copper ATPase (Atp7a) and metallothionein) in the duodenal epithelium of iron-deficient rats across several stages of postnatal development (Collins, J. F., Franck, C. A., Kowdley, K. V., and Ghishan, F. K. (2005) Am. J. Physiol., 288, G964–G971). We now report significant copper loading in the livers and intestines of iron-deficient rats. These findings are consistent with the hypothesis that there is increased intestinal copper transport during iron deficiency. We additionally found that hepatic Atp7b gene expression does not change with iron deficiency, suggesting that liver copper excretion is not altered. We have developed polyclonal antibodies against rat ATP7A, and we demonstrate the specificity of the immunogenic reaction. We show that the ATP7A protein is present on apical domains of duodenal enterocytes in control rats and on brush-border and basolateral membrane domains in iron-deprived rats. This localization is surprising, as previous in vitro studies have suggested that ATP7A traffics between the trans-Golgi network and the basolateral membrane. We further demonstrate that ATP7A protein levels are dramatically increased in brush-border and basolateral membrane vesicles isolated from iron-deficient rats. Other experiments show that iron refeeding partially corrects the hematological abnormalities seen in iron-deficient rats but that it does not ameliorate ATP7A protein induction, suggesting that Atp7a does not respond to intracellular iron levels. We conclude that ATP7A is involved in copper loading observed during iron deficiency and that increased intestinal copper transport is of physiological relevance, as copper plays important roles in overall body iron homeostasis. [ABSTRACT FROM AUTHOR]

Divalent metal transporter #1 (DMT1) is responsible for intestinal nonheme Fe apical uptake. However, DMT1 appears to have an additional function in Cu transport in intestinal cells. Because the liver has an essential role in body Cu homeostasis, we examined the potential involvement of Cu in the regulation of DMT1 expression and activity in Hep-G2 cells. Cells exposed to 10 µM Cu exhibited a 22-fold increase in Cu content and a twofold decrease in Fe content compared with cells maintained in 0.4 µM Cu. 64Cu uptake in Cu-deficient Hep-G2 cells showed a twofold decrease in Km compared with cells grown in 10 µM Cu. The decreased Km may represent an adaptive response to Cu deficiency. Cells treated with >50 µM Cu, showed an eightfold increase in cytosolic metallothionein. DMT1 protein decreased (35%), suggesting that intracellular Cu caused a reduction of DMT1 protein levels. Our data indicate that, as a result of Cu overload, Hep-G2 cells reduced their Fe content and their DMT1 protein levels. These findings strongly suggest a relationship between Cu and Fe homeostasis in Hep-G2 cells in which Cu accumulation downregulates DMT1 activity. [ABSTRACT FROM AUTHOR]

The cu-binding &beta-amyloid precursor protein (APP), and the amyloid Aβ peptide have been proposed to play a role in physiological metal regulation. There is accumulating evidenceo f an unbalance Cu homeostasis with a causative or diagnostic link to Alzheimer's disease. Whereas elevated Cu levels are observed in APP knockout mice, APP overexpression results in reduced Cu in transgenic mouse brain. Moreover, Cu induces a decrease in Aβ levels in APP-transfected cells in vitro. To investigate the influence of bioavailable Cu, transgenic APP23 mice received an oral treatment with Cu-supplemented sucrose-sweetened drinking water (1). Chronic APP overexpression per se reduced superoxide dismutase 1 activity in transgenic mouse brain, which could be restored to normal levels after Cu treatment (2). A significant increase of brain Cu indicated its bioavailability on Cu treatment in APP23 mice, whereas Cu levels remained unaffected in littermate controls (3). Cu treatment lowered endogenous CNS Aβ before a detectable reduction of amyloid plaques. Thus, AOPP23 mice reveal APP-induced alterations linked to Cu homeostasis, which can be reversed by addition of dietary Cu. [ABSTRACT FROM AUTHOR]

Members of the Cu transporter (Ctr) family have been reported to be part of the copper uptake machinery in several organisms. Recently it has been suggested that human Ctr1 (hCtr1) may act as a copper transporter in several tissues including the intestine. hCtr1 is a 190 amino acid protein and is predicted to have three transmembrane-spanning domains and exist in the plasma membrane as a homo-trimer. Ctr1-transfected cell lines exhibit saturable, pH-dependent Cu(I) uptake indicating a role in copper transport. Recent studies with Ctr1 knockout mice have highlighted an essential function in mammalian embryonic development since homozygous mutants die in utero. Heterozygotes are indistinguishable from wild-type littermates but have a severely reduced brain copper content, suggesting that Ctr1 is a key component of the copper uptake pathway in the brain. However, its role in other tissues remains elusive. [Copyright &y& Elsevier]

Determines the relative quantitative contributions of waterborne and dietary uptake rates for copper. Effects of waterborne copper preexposure on copper homeostasis; Time course of acute waterborne and dietary copper uptake; Uptake of waterborne copper using direct copper flux measurements.

Discusses the role of cellular transporters on copper transport at the cellular level. Mechanism of copper homeostasis; Interactions among passive and active membrane transport proteins, vesicles and soluble peptides; Functionality of cellular copper.

This study was undertaken to assess changes in zinc and copper homeostasis in human tissues that could be attributed to human exposure to environmental cadmium, using samples of lung, liver and kidney cortex of 61 Queensland residents, aged 2 to 89 years, who had died of accidental causes. None of the subjects were exposed to cadmium in the workplace. Levels of zinc in liver and kidney cortex samples showed inverse associations with donor age whereas zinc in lung only showed inverse association with gender. Lung zinc levels in females were 14% lower than in males. Zinc in liver and kidney cortex samples were found to exist in at least two pools; one was associated with cadmium that bound to metallothionein (MT) and the other was associated with non-MT bound copper. In liver, the amounts of zinc in the MT pool were smaller compared to those in non-MT pool given that only 7% of zinc variations were explained by cadmium whereas 22% of the liver zinc variations were accounted for by non-MT bound copper. In sharp contrast, larger amounts of zinc in kidney cortex samples were in the MT pool, compared to those in the non-MT pool given that cadmium was found to explain 69% of total zinc variation whereas copper explained only 17% of kidney zinc variations. The levels of copper in liver were found to be increased by 45–50% in subjects with high cadmium exposure level, compared to subjects of similar ages with medium exposure level. The levels of zinc and copper in kidney cortex samples in the subjects with high cadmium exposure were both found to be significantly elevated compared to those found in the medium-exposure group whereas copper contents were about 19–23% greater than in medium- as well as low-exposure groups. Taken together these results indicate increased sequestration of zinc and copper in liver and kidney cortex samples. The increases in metal sequestrations were observed in liver samples having cadmium contents of greater than 1 μg/g wet weight and in kidney cortex having cadmium contents of greater than 26 μg/g wet weight. Zinc and copper contents in lung of this sample group, however, were not associated with cadmium due probably to lower exposure levels compared to those of liver and kidney. [ABSTRACT FROM AUTHOR]

Comments on studies dealing with changes in zinc and copper levels in patients with Alzheimer's disease. Existence of a number of drugs with therapeutic activity based partly on active-site metal co-ordination or complexation; Alteration of metal homeostasis in Alzheimer's disease (AD); Most important mechanism for neuronal death in AD.

A correction to the article "Perturbation of Copper (Cu) Homeostasis and Expression of Cu-Binding Proteins in Cadmium-Resistant Lung Fibroblasts," by Denise K. Chou and colleagues is presented.